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This retrospective study reviews outcomes of 281 pediatric patients with bronchopulmonary dysplasia (BPD) managed with extracorporeal life support (ECLS). Data from 1982 to 2018 from the Extracorporeal Life Support Organization (ELSO) registry were queried for children aged 60 days to 18 years with a prior diagnosis of BPD, and all patients with secondary pulmonary hypertension (PH) were identified. Overall survival of patients with and without PH was 86.7% and 68.0%, respectively (p = 0.23). There was no report of patients with PH before 2004. Patients with BPD + PH were more likely to have associated intraventricular hemorrhage (p = 0.002) and retinopathy of prematurity (p = 0.05), as well as a greater reported use of sildenafil (p = 0.0001) and milrinone (p = 0.008) before ECLS. The most common primary diagnosis in patients with BPD was viral respiratory infection (45.3%) and in patients with BPD + PH was respiratory failure without mention of infection (40.0%). Inotrope use was the most common complication reported (36.7%) with survival of 54.4%. We conclude that data from the ELSO registry demonstrate reasonable survival in both, patients with BPD and BPD + PH. Thus, patients with BPD and associated PH should be considered candidates for ECLS.

This study compared the effect of container material type on macronutrient changes in human breast milk (HBM) during frozen storage. HBM was collected from breastfeeding mothers and baseline macronutrients were analyzed and recorded. The HBM was aliquoted into milk storage containers of five commonly used materials (low-density polyethylene (LDPE), polypropylene (PP), glass, stainless steel, and silicone). The samples were frozen in a standard freezer (-20°F) for 30, 60, and 180 days prior to thawing and retesting macronutrient values. In the 155 samples analyzed, macronutrient changes among different types of storage materials were insignificant at 30 and 60 days of frozen storage. When comparing macronutrients at baseline to 180 days, there was a significant decrease in protein value over time in LDPE containers as compared to silicone containers (p=0.001). Likewise, there was a significant decrease in total calories from baseline to 180 days in both PP and LDPE containers compared to silicone (p=0.046 and 0.013, respectively). While not significant for short-term storage, HBM has losses of macronutrients (protein) with long-term storage in LDPE and PP plastics. These differences could have major nutritional impact on growth, particularly to infants born prematurely.

Abnormally high serum ferritin levels have been reported during pediatric ECMO, attributed to frequent red blood cell transfusion and suggestive of iron overload. However, the utility of ferritin for diagnosing iron overload is complicated by its response as an acute-phase reactant. In this study, we aimed to assess the utility of ferritin for diagnosing ECMO-related iron overload, with secondary aims of understanding its relationship with inflammation and erythropoiesis. Ferritin was elevated in all pediatric ECMO runs (median 459 ng/ml, IQR = 327.3-694.4). While intermittent elevations in serum iron were observed, all normalized prior to decannulation. Unreported previously, erythropoietin (EPO) remained well above normative values prior to and throughout ECMO runs, despite frequent transfusion and exposure to hyperoxia. Ferritin correlated poorly with serum iron [r(80) = 0.05, p = 0.65], but correlated well with IL-6 [r(76) = 0.48, p < 0.001] and EPO [r(81) = 0.55, p < 0.001]. We suggest that serum ferritin is a poor biomarker of iron overload in ECMO patients, and that future investigation into its relationship with EPO is warranted.

Premature infants have altered glucose regulation early in life and increased risk for diabetes in adulthood. Although prematurity leads to an increased risk of diabetes and metabolic syndrome in adult life, the role of hepatic glucose regulation and adaptation to an early extrauterine environment in preterm infants remain unknown. The purpose of this study was to investigate developmental differences in glucose metabolism, hepatic protein content, and gene expression of key insulin-signaling/gluconeogenic molecules. Fetal baboons were delivered at 67%, 75%, and term gestational age and euthanized at birth. Neonatal baboons were delivered prematurely (67% gestation), survived for two weeks, and compared with similar postnatal term animals and underwent serial hyperinsulinemic-euglycemic clamp studies. Premature baboons had decreased endogenous glucose production (EGP) compared with term animals. Consistent with these results, the gluconeogenic molecule, phosphoenolpyruvate carboxykinase messenger RNA, was decreased in preterm baboons compared with terms. Hepatic insulin signaling was altered by preterm birth as evidenced by decreased insulin receptor–β, p85 subunit of phosphoinositide 3-kinase, phosphorylated insulin receptor substrate 1, and Akt-1 under insulin-stimulated conditions. Furthermore, preterm baboons failed to have the normal increase in glycogen synthase kinase-α from fetal to postnatal life. The blunted responses in hepatic insulin signaling may contribute to the hyperglycemia of prematurity, while impaired EGP leads to hypoglycemia of prematurity.

Background Although studies involving preterm infants ≤34 weeks gestation report a decreased incidence of patent ductus arteriosus after antenatal betamethasone, studies involving younger gestation infants report conflicting results. Methods We used preterm baboons, mice and humans (≤276/7 weeks gestation) to examine betamethasone’s effects on ductus gene expression and constriction both in vitro and in vivo. Results In mice, betamethasone increased the sensitivity of the premature ductus to the contractile effects of oxygen without altering the effects of other contractile or vasodilatory stimuli. Betamethasone’s effects on oxygen sensitivity could be eliminated by inhibiting endogenous prostaglandin/nitric oxide signaling. In mice and baboons, betamethasone increased the expression of several developmentally-regulated genes that mediate oxygen-induced constriction (K+ channels) and inhibit vasodilator signaling (phosphodiesterases). In human infants, betamethasone increased the rate of ductus constriction at all gestational ages. However, in infants born ≤256/7 weeks gestation, betamethasone’s contractile effects were only apparent when prostaglandin signaling was inhibited, whereas, at 26-27 weeks gestation betamethasone’s contractile effects were apparent even in the absence of prostaglandin inhibitors. Conclusions We speculate that betamethasone’s contractile effects may be mediated through genes that are developmentally regulated. This could explain why betamethasone’s effects vary according to the infant’s developmental age at birth.

The aim of the study was to determine the acute and long-term outcomes of preterm infants treated with an intravenous fish oil-based lipid emulsion (FishLE) for parenteral nutrition-associated liver disease (PNALD).Preterm infants 14 days to 24 months of age with anatomic short gut or severe intestinal dysmotility, serum direct bilirubin ≥4 mg/dL, and requiring60% calories from parenteral nutrition were eligible. Enrolled infants received 1 g · kg · day of FishLE until resolution of direct hyperbilirubinemia or return of enteral nutrition. Acute clinical effects and biochemical markers of liver function were monitored. Growth and developmental scores at 6 and 12 months postmenstrual age (PMA) were assessed and compared with controls matched by gestational age (GA).Thirteen patients with mean GA of 28 ± 4 weeks were treated and compared with 119 GA-matched controls. Their mean direct bilirubin was 9.8 ± 6.4 mg/dL at enrollment. All infants had resolution of cholestasis after study completion. There were no acute adverse events, deaths, or liver/intestinal transplants. Weight and head circumference were similar between FishLE-treated patients and controls at 6- and 12-month PMA. Cognitive and motor scores were decreased at 6 and 12 months PMA in FishLE-treated infants. Logistic regression analysis showed that prolonged hospitalization was detrimental to cognitive and motor development, whereas treatment was not.The use of intravenous FishLEs in premature infants appears to be safe and reverses PNALD despite significant liver disease and intestinal failure. This therapy should be used in preterm infants with PNALD and followed long term to evaluate development.

Premature baboons exhibit peripheral insulin resistance and impaired insulin signaling. 5' AMP-activated protein kinase (AMPK) activation improves insulin sensitivity by enhancing glucose uptake (via increased glucose transporter type 4 [GLUT4] translocation and activation of the extracellular signal-regulated kinase [ERK]/ atypical protein kinase C [aPKC] pathway), and increasing fatty acid oxidation (via inhibition of acetyl-CoA carboxylase 1 [ACC]), while downregulating gluconeogenesis (via induction of small heterodimer partner [SHP] and subsequent downregulation of the gluconeogenic enzymes: phosphoenolpyruvate carboxykinase [PEPCK], glucose 6-phosphatase [G6PASE], fructose- 1,6-bisphosphatase 1 [FBP1], and forkhead box protein 1 [FOXO1]). The purpose of this study was to investigate whether pharmacologic activation of AMPK with AICAR (5-aminoimidazole-4-carboximide riboside) administration improves peripheral insulin sensitivity in preterm baboons. 11 baboons were delivered prematurely at 125±2 days (67%) gestation. 5 animals were randomized to receive 5 days of continuous AICAR infusion at a dose of 0.5 mg·g-1·day-1. 6 animals were in the placebo group. Euglycemic hyperinsulinemic clamps were performed at 5±2 and 14±2 days of life. Key molecules potentially altered by AICAR (AMPK, GLUT4, ACC, PEPCK, G6PASE, FBP1, and FOXO1), and the insulin signaling molecules: insulin receptor (INSR), insulin receptor substrate 1 (IRS-1), protein kinase B (AKT), and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) were measured using RT-PCR and western blotting. AICAR infusion did not improve whole body insulin-stimulated glucose disposal in preterm baboons (12.8±2.4 vs 12.4±2.0 mg/(kg·min), p = 0.8, placebo vs AICAR). One animal developed complications during treatment. In skeletal muscle, AICAR infusion did not increase phosphorylation of ACC, AKT, or AMPK whereas it increased mRNA expression of ACACA (ACC), AKT, and PPARGC1A (PGC1α). In the liver, INSR, IRS1, G6PC3, AKT, PCK1, FOXO1, and FBP1 were unchanged, whereas PPARGC1A mRNA expression increased after AICAR infusion. This study provides evidence that AICAR does not improve insulin sensitivity in premature euglycemic baboons, and may have adverse effects.

The pathogenesis of bronchopulmonary dysplasia (BPD), a devastating lung disease in preterm infants, includes inflammation, the mechanisms of which are not fully characterized. Here we report that the activation of the NLRP3 inflammasome is associated with the development of BPD. Hyperoxia-exposed neonatal mice have increased caspase-1 activation, IL1β and inflammation, and decreased alveolarization. Nlrp3(-/-) mice have no caspase-1 activity, no IL1β, no inflammatory response and undergo normal alveolarization. Treatment of hyperoxia-exposed mice with either IL1 receptor antagonist to block IL1β or glyburide to block the Nlrp3 inflammasome results in decreased inflammation and increased alveolarization. Ventilated preterm baboons show activation of the NLRP3 inflammasome with increased IL1β:IL1ra ratio. The IL1β:IL1ra ratio in tracheal aspirates from preterm infants with respiratory failure is predictive of the development of BPD. We conclude that early activation of the NLRP3 inflammasome is a key mechanism in the development of BPD, and represents a novel therapeutic target for BPD.